Human Molecular Genetics Advance Access originally published online on December 21, 2006
Human Molecular Genetics 2007 16(5):453-462; doi:10.1093/hmg/ddl462
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Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1
1 Department of Molecular Medicine and 2 Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland, 3 Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland, 4 Department of Genetics and Development, Department of Psychiatry, Columbia Genome Center, Columbia University, New York, NY, USA, 5 Division of Medical Genetics, New York State Psychiatric Institute, New York, NY, USA, 6 Finnish Genome Center and 7 Department of Medical Genetics, University of Helsinki, Helsinki, Finland and 8 The Broad Institute, MIT, Boston, MA, USA
* To whom correspondence should be addressed at: Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland. Tel: +1 358947448393; Fax: +1 358947448480; Email: leena.peltonen{at}ktl.fi
Received November 20, 2006; Accepted December 4, 2006
We have previously reported a robust association between an allelic haplotype of ‘Disrupted in Schizophrenia 1’ (DISC1) and schizophrenia in a nationwide collection of Finnish schizophrenia families. This specific DISC1 allele was later identified to associate with visual working memory, selectively in males. DISC1 association to schizophrenia has since been replicated in multiple independent study samples from different populations. In this study, we conditioned our sample of Finnish families for the presence of the Finnish tentative risk allele for DISC1 and re-analyzed our genome-wide scan data of 443 markers on the basis of this stratification. Two additional loci displayed an evidence of linkage (LOD > 3) and included a locus on 16p13, proximal to the gene encoding NDE1, which has been shown to biologically interact with DISC1. Although none of the observed linkages remained significant after multiple test correction through simulation, further analysis of NDE1 revealed an association between a tag-haplotype and schizophrenia (P = 0.00046) specific to females, which proved to be significant (P = 0.011) after multiple test correction. Our finding would support the concept that initial gene findings in multifactorial diseases will assist in the identification of other components of complex genetic etiology. Notably, this and other converging lines of evidence underline the importance of DISC1-related functional pathways in the etiology of schizophrenia.
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